The long-term goal of the PI is to determine autonomic and vascular mechanisms engaged by hypoxic stress, and to explore their role in disease. In this project we will examine the effects of acute and intermittent hypoxia, two prevalent types of physiologic stress, on neurocirculatory control. Hypoxic stress is common in a variety of disease states and in smokers, and intermittent hypoxia is characteristic of obstructive sleep apnea. These conditions are marked by increased cardiovascular risk. Skeletal muscle hypoxia is also present during exercise, yet exercise training appears to improve vascular and autonomic reflex function. It has been shown that systemic and regional hypoxia (i.e., ischemia) exert their effects on the circulation via integrated but at times opposing influences on the autonomic nervous system and local metabolic control. Preliminary data from our laboratory suggest that in healthy humans intermittent hypoxia elicits sustained sympathetic activation and enhanced reflex responses to hypoxia. Because the antioxidant ascorbic acid attenuates the sympatho- excitatory effect of intermittent hypoxia, oxidative stress may be responsible. We also found that sympathetic reflex responses to hypoxia are enhanced in patients with sleep apnea and are normalized in part by continuous positive airway pressure therapy. However, despite increased sympathetic vasoconstrictor nerve traffic and enhanced chemoreflex activation, the vasodilation induced by acute hypoxia is preserved in patients with sleep apnea. Collectively, these findings support the central hypothesis that intermittent hypoxia alters sympathetic activity and reflex function, and evokes vascular adaptations, possibly via oxidative stress. The specific aims of this proposal are to determine whether: (1) experimental intermittent hypoxia or nocturnal intermittent hypoxia in patients with sleep apnea alters sympathetic reflex function that can be restored by antioxidant interventions (administration of ascorbic acid, exercise training); (2) skeletal muscle vascular adaptations to intermittent hypoxic stress are in part due to an enhanced role of endothelial vasodilator systems such as endothelium-derived hyperpolarizing factor (EDHF); and, (3) cigarette smoking alters neurocirculatory control that can be restored in part by antioxidant interventions. The proposed studies expand the scope of our prior work on neurocirculatory regulation during hypoxia and will provide new insight into the mechanisms that link intermittent hypoxia to adverse cardiovascular outcomes. PUBLIC HEALTH RELEVANCE: This research examines mechanisms that govern the control of peripheral blood flow during exposure to physiological stress associated with low oxygen supply. These mechanisms appear to be altered in important ways in highly common conditions such as obstructive sleep apnea {and in smokers.} New insight into these processes will help us better understand whether and how these mechanisms contribute to disease and will allow us to design better therapies and preventive measures.